The cause of the sudden infant death syndrome (SIDS), which claims 8000 lives each year, is known. A widely-held hypothesis is that SIDS is due to an abnormality in brainstem sites involved in cardiorespiratory regulation during sleep and occurs during a critical period in their maturation and integration. Since a qualitative brainstem abnormality is not seen by conventional histopathologic criteria, we are testing the hypothesis that there is a quantitative brainstem pathology in SIDS. We are quantitating selected cellular and chemical parameters of brainstem maturation and injury with 3-dimensional (3-D), computer-based methods of developed in the Department of Neuroscience, Children's Hospital, Boston. We are examining several parameters relative to one another, as no one single parameter carries enough information. Our specific aims are to test critically whether there is in SIDS victims: 1) a quantitative increase in the density of reactive astrocytes ("scar cells") in brainstem nuclei related to cardiorespiratory and/or sleep-waking regulation; 2) a deviation in number, density and/or size of neuronal subclasses in the same nuclei; 3) axonal degeneration in relevant brainstem pathways; and/or 4) a quantitative deviation in the developmental profile a postsynaptic receptors of selected neurotransmitter (NT) systems involved in cardiorespiratory and sleep- waking regulation. We also intend: 5) to correlate brainstem findings with systemic abnormalities, e.g., hepatic erythropoiesis, determined by collaborators in the same study population. Two further aims that are fundamental to SIDS data collection are: 6) establish a computerized, 3-D data-base describing the cyto- and chemoarchitectonic organization of the human fetal and infant brainstem; and 7) develop efficient strategies for 3-D sampling in structurally and neurochemically heterogeneous brainstem nuclei. Our pilot cytological data suggest that there is almost a 50% difference in opiate receptor binding in the nucleus of the tractus solitarius, the major integrative site of cardiorespiratory reflexes. These potentially important leads warrant intense pursuit, as undisputable evidence for a brainstem abnormality could provide a critical step towards discovering the cause of SIDS.